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Success story: Prion hypothesis challenged by new Sheep study

Despite the fact that the Nobel Prize was awarded for the prion hypothesis, there remains the possibility that the infectious agent behind diseases such as mad cow, scrapie and variant Creutzfeldt-Jakob disease might not necessarily be rogue prion protein. The findings of the SC GUT project, funded for five years via the European Commission’s Fifth Framework Programme, show that there is a need to remain diligent and open minded when investigating the causes of this group of diseases.

Tubes containing the main compounds used in the project
© Dr. Arild Espenes ( Norwegian School of Veterinary Science)

Scrapie in sheep is problem through most of the world and is the most widespread TSE in Europe. It is generally considered, but not proven, to be the source of the BSE epidemic and control and eradication of TSE in small ruminants is one of the top priorities in the EU. The SC GUT project, addresses key issues related to the pathogenesis of scrapie and BSE in sheep. By studying the problem of scrapie in sheep, this project helps to provide tools for early detection of TSEs which will be a key to the control of diseases that are a significant threat to human food safety. The confirmation of BSE in a goat in France in January 2005 added greater emphasis to the need for this type of research.

Better knowledge of TSE in sheep

The SC GUT project studies the early pathogenesis of scrapie and of bovine spongiform encephalopathy (BSE) in sheep and mice, using a combination of approaches involving novel experimental methods and includes the experimental oral infection of scrapie-free sheep and access to scrapie-infected flocks of PrP-genotyped sheep. These studies will result in a better understanding of the early pathogenesis of scrapie and BSE and this understanding will, in turn, contribute to the better application of diagnostic methods and control strategies, leading to safer food sources for consumers.

Prion proteins hypothesis in question

The infectious agent behind mad cow, scrapie and variant Creutzfeldt-Jakob disease is generally believed to be rogue prion proteins. Although deformed prions are a characteristic of these diseases however, it is possible that they are not the initial infectious agent. This theory is based on how these proteins are absorbed in the sheep gut. The scientists inoculated sheep intestines with brain extracts containing the abnormal form of the prion protein (PrP) believed to cause the neurodegenerative disease. Surprisingly, the inoculated prion proteins were only detected for a short time (3.5 hours) in the wall of the gut and not in sites where disease generated prion protein accumulated, i.e., prion proteins generated by the disease itself first accumulated one month after inoculation and appeared at sites different from those sites where the inoculated prion protein was seen to be absorbed. In addition, experiments suggest that in the normal animal almost all ingested prions will be digested before it could be absorbed by the gut – supporting the theory that prions do not cause the disease by passing through the gut wall.

Diagram showing relevant anatomical features of distal ileum, and observed routes of transport of inoculum, and a separate, inferred route of transport of infectivity.
Jeffrey, M., Gonzalez, L., Espenes, A., Press, C.M., Martin, S., Chaplin, M., Davis, L., Landsverk, T., MacAldowie, C., Eaton, S. and McGovern, G., Transportation of prion protein across the intestinal mucosa of scrapie-susceptible and scrapie-resistant sheep, Journal of Pathology, 2006, 209 (1): 4-14.
© Pathological Society of Great Britain and Ireland. Permission granted by John Wiley & Sons Ltd on behalf of PathSoc.

New mechanisms of infection

The new discovery does not rule out the possibility that prion proteins, if absorbed in sufficient amounts, might still cause disease, or it may be that prions directly infect nerve endings by some other mechanism. The scientists involved in SC GUT, however, contemplated another intriguing possibility - that the prion hypothesis might not be the correct explanation for TSE infection. Further investigation of the causes of this group of diseases is, therefore, needed.

QLK5-CT-2001-02332, SC-GUT,

Professor Charles McL. Press
Norwegian School of Veterinary Science
Box 8146 Dep., 0033 Oslo
Telephone: (+47) 22597037
Telefax: (+47) 22597086
E-mail address:


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